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The autonomic innervation of human airways
•Parasympathetic innervations: innervates bronchial
smooth muscle. Causes contraction of bronchial smooth
muscle, and increase mucosal secretion. (M3 receptors)
•Sympathetic innervations: innervate tracheobronchial
blood vessels and glands but not airway smooth muscle,
and increase mucociliary clearance.
Inhibitory Non-noradrenergic non-cholinergic
nerves (NANC ): releasing vasoactive intestinal peptide
and nitric oxide, are important neural bronchodilator.
Excitatory NANC nerves cause neuroinflammation by
releasing tachykinins: substance P and neurokinin A.
3. Commonly encountered respiratory diseases
Asthma
Chronic obstructive pulmonary disease (COPD)
Allergic rhinitis
Cough
• Adequately controlled through a combined approach of
appropriate lifestyle changes and medication mgt
4. Asthma
Clinical features of asthma
Asthma is defined as recurrent reversible airway
obstruction, with attacks of wheeze, shortness of breath and
often nocturnal cough. Severe attacks cause hypoxaemia
and are life-threatening.
Essential features include:
– airways inflammation, which causes
– bronchial hyper-responsiveness, which in turn results in
– recurrent reversible airway obstruction. 4
5. • Narrowing of the airway in acute asthmatic attacks results
from
Contraction of the airway smooth muscle
Thickening of the bronchial mucosa
» Edema
» Lymphocyte and eosinophils infiltration
» Hyperplasia of secretory, vascular, and smooth
muscle cells
Pathological features
» Lymphocytic, eosinophilic inflam. of the bronchial
mucosa
» Deposition of collagen beneath the epithelium’s lamina
reticularis 5
7. Risk Factors
• Bronchospasm can be provoked by non-allergenic stimuli
–Genetic
–Exercise
–Cold air
–Sulfur dioxide
–Drug induced asthma
–Rapid respiratory maneuvers, or
–allergen ( proteins from house dust mites,
cockroach, cat dander, molds, and pollen)
• Drugs can be delivered
– Topically to the nasal mucosa
– Inhaled into the lungs, or
– Given orally or parenterally for systemic 7
9. Control of bronchial smooth muscle contraction
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Bronchodilation is promoted by cAMP. Intracellular levels of cAMP can be increased by
-adrenoceptor agonists, which increase the rate of its synthesis by adenylyl cyclase
(AC); or by phosphodiesterase (PDE) inhibitors such as theophylline, which slow the
rate of its degradation. Bronchoconstriction can be inhibited by muscarinic antagonists
and possibly by adenosine antagonists.
10. Treatment of asthma
Bronchodilators
Beta2 adrenoreceptor agonists
– MOA
• Activation of B2 – Receptors ↑ cAMP
bronchial smooth muscle relaxation
• Inhibits the function of numerous inflammatory
cells
»Mast cells, basophils, eosinophils,
neutrophils, and lymphocytes
10
11. Treatment of asthma
1. Short acting B2 agonists
• Salbutamol, Terbutaline, Pirbuterol, Metaproterenol
• Onset of action within 5 minutes after inhalation
• Duration of action spans 2-6 hrs
• Available in Metered-dose inhalers and nebulized
aerosols
• Rapid symptomatic relief of dyspnea associated with
asthmatic attack bronchoconstriction
• Salbutamol, Terbutaline, and Metaproterenol are also
11
12. Treatment of asthma
2. Long- acting B2- agonists
Salmeterol & Formoterol
• Long duration of action ( > 12 hours)
• Used for maintenance Rx of asthma
» Taken Regularly
Agent of choice for nocturnal asthma
• To significantly inhibit the inflammation a
combination with steroids is recommended
Salmeterol and fluticasone
Formoterol and budesonide
12
13. Treatment of asthma
Adverse Effects of B2- agonists
• Inhalational use → adverse effects are uncommon
• Oral & parentral use
– if dosage is excessive
» angina pectoris
» tachyarrhythmias
» Tremor
13
14. Treatment of asthma
Non B2 specific bronchodilators
Epinephrine ( Adrenaline)
• Effective and rapidly acting bronchodilator (sc or
inhalation)
• Peak bronchodilation is achieved 15 minutes after
inhalation and lasts 60-90 minutes
• Its use in asthma has been displaced by selective agents
» Reserved to treat acute vasodilation, shock
and bronchospasm of anaphylaxis
14
15. Treatment of asthma
Non B2 specific bronchodilators…
Ephedrine
• Mixed-acting sympathomimetic drug
• Ephedrine is now used infrequently to treat asthma
• As compared to epinephrine
Ephedrine has a longer duration, oral activity,
more pronounced central effect, much lower
potency
Isoproterenol
• Very potent bronchodilator; when inhaled, maximal
effect with in 5 minutes, has 60-90 minute duration
of action 15
16. Treatment of asthma
Methylxanthines
Used only when other drugs such as beta 2 specific
agents are ineffective.
Theophylline, caffeine,theobromine
Theophylline
• MOA
a) By inhibiting PDE ↑cAMP
bronchodilation
o↓ Release of inflammatory mediators
b) Inhibition of cell surface receptors for
adenosine
16
18. Treatment of asthma
• Therapeutic uses
Relieve airway obstruction in acute asthmatic attack
Add-on therapy to inhaled corticosteroids and long-
acting β2 agonists (long term controller)
Appropriate for noctural asthma (b/c of prolonged
effects)
IV theophylline (Aminophylline) is employed in
emergencies.
• Toxicity
• has a narrow therapeutic window: cardiac dysrhythmia,
seizures and gastrointestinal disturbances
Most likely at plasma levels > 40mg/L
» Ventricular arrhythmia
» Convulsions
» Headache, nausea, vomiting 18
19. Treatment of asthma
• Other preparations:
Aminophylline, LD 5.7 mg/kg, MD 5mg/kg
(Theophylline +Ethylene diamine)
– More water soluble than theophylline
Theophendrine (Theophylline + Ephedrine), (11mg
+ 120mg) P.O. BID OR TID
• Drug Interactions
Drugs that ↓ theophylline levels
• Phenobarbitone Phenytoin,
carbamazepine,rifampicin
Drugs that ↑ theophylline levels
19
20. Anticholinergic Agents
• Ipratropium bromide, tiotropium
• Available for inhalational administration
• M3 receptor antagonism is responsible for the
bronchodilation
• Slow and low intensity bronchodilation
• Combined use with β2-agonist provides better
outcomes
• Tiotropium has long duration of action (24 hrs duration)
Improve functional capacity of pts with COPD
=/Most common side effect is dry mouth 20
21. Treatment of asthma
Corticosteroids
• The most effective drugs available for long term control
• MoA: Act primarily by suppressing:-
» Synthesis & release of inflammatory mediators
» Infiltration & activation of inflammatory cells
» Edema of the air way mucosa (2o to vascular
permeability)
» Reduces bronchial hyperreactivity
↑number of B2 adrenoceptors ↑ responsiveness to
agonist
21
22. Treatment of asthma
Rout of therapy:
1) Inhalational therapy
• Considered 1st line therapy
• Low risk
• Should be used with B2- agonists
2) Oral therapy
• For pts with severe asthma
• Duration should be as short as possible
(toxicity)
3)Injectable
Adverse Effects:
a) Inhalational
• Generally devoid of serious toxicity
Oropharyngeal candidiasis 22
23. Treatment of asthma
b) Oral
• Used for > 15 days can be hazardous
– Osteoporosis
– Hyperglycemia
– PUD
– Adrenal suppression
– Suppression of growth in children
23
25. Severe acute asthma (status
Asthmaticus)
• Medical emergency requiring hospitalization
• Treatment includes oxygen
• Inhalation of salbutamol given by nebulizer,
and intravenous hydrocortisone followed by a
course of oral prednisolone
• Additional measures occasionally used include
nebulised ipratropium, intravenous
salbutamol or aminophylline, and antibiotics
(if bacterial infection is present)
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26. Treatment of asthma
Mast cell stabilizers
• Cromolyn Sodium, nedocromil
Very safe & effective for prophylaxis of asthma
Administered by inhalation
MoA
Acts by stabilizing the cytoplasmic membrane ↓
release of mediators
Inhibits activation of other inflammatory cells
Chronic administration ↓ Inflammation &
bronchial hyperreactivity
26
27. Treatment of asthma
• Cromolyn Sodium, nedocromil
• Therapeutic uses:
» Asthma (long term controller)
» Exercise, unavoidable allergen exposure
induced asthma (prophylaxis)
» Allergic rhinitis
• Adverse effects
Throat irritation, cough and mouth dryness, and
rarely chest tightness and wheezing
27
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Leukotriene Antagonists
Leukotrienes are mediators released from mast cells
upon contact with allergens.
Contribute powerfully to both inflammation and
bronchoconstriction
Can either block the synthesis of leukotrienes or
block their receptors.
Zileuton (Zyflo) is the prototype of those that block
the synthesis of leukotrienes
Zafirlukast (Accolate) is the prototype of those that
block their receptors
29. STG asthma
• First line
• Salbutamol Salbutamol, 200 micrograms, 2 puffs
/5min
• Alternatives
• Aminophylline, 5mg/kg by slow I.V. push over 5
minutes, I.V. infusion at 0.6 mg/kg/hr
• OR
• Adrenaline, 1:1000, 0.5ml sc. Repeat after ½ to 1
hour if patient doesn’t respond.
• If seviere, Aminophylline + Hydrocortisone , 200
mg IV stat OR Prednisolone, 40-60 mg P.O 5-7 ds
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CHRONIC OBSTRUCTIVE PULMONARY DISEASE (CO
Cigarette smoking is the main cause
Clinical features. morning cough during the winter,
often initiated by a cold. There is progressive
breathlessness, airflow obstruction
Pathogenesis. There is small airways fibrosis, resulting
in obstruction, and/or destruction of alveoli and of elastin
fibres in the lung parenchyma. The latter features are
hallmarks of emphysema,
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Principles of treatment.
•Stopping smoking,
•Short- and long-acting inhaled
bronchodilators (ipratropium, salbutamol )
•Long-term oxygen therapy
•Broad-spectrum antibiotics (e.g.
cefuroxime)
•glucocorticoid (intravenous hydrocortisone
or oral prednisolone)
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Allergic rhinitis
Rhinitis is an inflammation of the mucous membranes of
the nose and is characterized by
sneezing
itchy nose/eyes,
watery rhinorrhea, and
nasal congestion
Combinations of
oral antihistamines(loratadine,and fexofenadine,
Cetrizine, 10mg BID, Dexchlorpheniramine
maleate,: 6mg P.O. BID), Chlorpheniramine 4mg
bid with
decongestants(Xylometazoline, 2 - 3 drops).
Corticosteroids (Beclomethasone) and Cromolyn can
34. What is cough ?
It’s a protective reflex – for expulsion of
respiratory secretions and foreign particles
from air passages
Respiratory secretions !
Stimulation of mechano or chemoreceptor –
throat, respiratory passages and stretch
receptors in the lungs
Afferent fibres in vagus & sympathetic -
impulses to cough center – medulla
35. Cough – Types and Merits
Non-productive (Dry Cough) and Productive
Nonproductive ones need suppression –
cerebral hypoxia, rupture of bullas and fracture
ribs etc.
Productive – needs to clear airway
May be harmful if suppressed !
Amount of product Vs effort of coughing
Most of the time, coughing is beneficial
Removes excessive secretions
Removes potentially harmful foreign substances
In some situations, coughing can be harmful, such as after
hernia repair surgery
37. Cough – Drugs (Nonspecific)
1. PHARYNGEAL DEMULCENTS: Lozenges, cough drops,
linctuses glycerine and liquorice
2. EXPECTORANTS: (MUCOKINETICS – secretion
enhances):
a) Secretion Enhancers: Sodium and Potassium citrate, KI,
Guaiphenesin (Glyceryl guaicolate), Vasaka, Ammonium
chloride
b) Mucolytics: Bromhexine, Ambroxol, Acetylcysteine,
Carbocysteine
3. CENTRAL COUGH SUPPRESSANTS:
a) Opioids: Codeine, Pholcodeine
b) Nonopioids: Noscapine, Dextromethorphan
c) Antihistamines: Chlorpheniramine maleate,
Diphenhydramine,promethazine
4. ADJUVANT: Salbutamol, Terbutaline
38. Drugs of Cough – Demulcents and
Expectorants
Demulcents
Soothing effect and symptomatic relief – reduce
afferent impulses - act by increasing flow of
saliva
Expectorants (Mucokinetics)
1. Increase Bronchial Secretion – Na and K
citrate
2. Irritation of Bronchial mucosa – Iodides
3. Enhance Bronchial secretions (and
mucociliary functions) – Guaiphenesin,
Vasaka
4. Ammonium salts – nauseating, reflex
stimulation of bronchial secretion
39. Bromhexine: Derivative of Adhatoda vasica
(Vasaka) – increases bronchial secretion
Depolymerises mucopolysaccharides in bronchial
secretions – directly or by liberating lysosomal enzyme
Fibres of sputum breaks down
Useful in mucus plug
Ambroxol: Similar to Bromhexine
Acetylcysteine: Breaks sulfide bond in
mucopolysaccharides of bronchial secretions –
Respiratory tract administration
Carbocysteine: Similar to acetylcysteine –
administered orally
Actions of Drugs of Cough – Mucolytics
40. 40
Antitussives
Act in the brain stem, depressing cough center
Used only for dry (unproductive) cough
Can cause harmful sputum thickening and retention
Should not be used for the cough associated with asthma
Drugs:
Dextrometorphan, Codeine, hydrocodone, hydromorphone
Cough mixtures may also contain
Antihistamines: chlorpheniramine, diphenhydramine
Decongestants: pseudoephedrine, phenylephrine
Wednesday, October 26,
2022
41. Antitussive - Codeine
Opioid – opium alkaloid – methyl morphine
Partly converts to Morphine
Less potent than Morphine and degree of
analgesia is equivalent to Aspirin (60 mg)
But, more selective for cough centers and
action lasts for 6 Hours
Blocked by Naloxone
Low abuse liability
Drawbacks: constipation, respiratory
depression and drowsiness (Higher doses)
PHOLCODEINE: No analgesia or addicting
property – longer acting
42. Cough Drugs - Nonopioids
Noscapine: Opium alakaloid
Depresses cough, but no analgesic, narcotic or
dependence liability
Equipotent with codeine – spasmodic cough
Histamine release – no in asthma
Dextromethorphan:
Synthetic – d-isomer (antitussive) and l-isomer (analgesic)
Effective as codeine but no addicting and constipating effect
– No impairment of mucocilliary function
But, dissociative effect – recreational drug?
In Combination – Paracetamol (acetaminophen)
43. Cough Drugs
Antihistamine:
Chlorpheniramine, Diphenhydramine and
Promethazine
MOA: Sedative and anticholinergic
Useful in allergic cough
Bronchodilators:
Bronchospasm can induce cough and constriction
Hyperactivity of Bronchial smooth muscles
Bronchodilators – relieves cough and improves
clearance during cough
